Venlafaxine is the INN for 1-(2-dimethylamino-1 -(4-methoxyphenyl)-ethyl)-cyclohexanol. Its racemic hydrochloride salt is included in a formulation which is commercially available under the trade name Effexor. Venlafaxine is used in form of its salt as this allows an easy preparation of various types of formulations, such as tablets, capsules, lozenges, powders, and the like for oral administration.
Venlafaxine was first described in EP-A-112 669. According to this document venlafaxine is prepared by N-methylation of the precursor N,N-didesmethyl venlafaxine using formaldehyde and formic acid. The venlafaxine is then recovered by chromatography to remove the by-product spiro venlafaxine and it is subsequently converted into venlafaxine hydrochloride using 4N isopropanolic HCl. The yield of the product, however, was very low.
In Journal of Medicinal Chemistry, 1990, Vol. 33, No. 10 (2899-2905) the synthesis of venlafaxine from p-methoxybenzylcyanide is disclosed and it involves N-methylation by a modified Eschweiler-Clark procedure using formaldehyde and formic acid. A solution of venlafaxine in ethyl acetate is treated with 2-propanolic HCl and the obtained venlafaxine hydrochloride is then recrystallized from methanovethyl acetate under unspecified conditions. The calculated yield for the crude product is 80%, based on N,N-didesmethyl venlafaxine.
The existence of certain polymorphs of venlafaxine hydrochloride is mentioned in EP-A-797 991. In this document, two polymorphs are described one of them being regarded as a kinetical product of the crystallization process. It is also disclosed that on heating in the crystallization solvent one of the polymorph is transformed into the other polymorph. It is, however, not disclosed which solvent is used for recrystallization.
Later on, various patent applications were published disclosing different polymorphic forms of racemic venlafaxine hydrochloride, e.g. designated as Form I, II, III and IV and A, B, C and D, and processes for their preparation.
WO 02/45658 describes the preparation of crystalline venlafaxine from N,N-didesmethyl venlafaxine hydrochloride and processes for producing crystalline venlafaxine hydrochloride forms I, II, III and IV. The products obtained were often mixtures of polymorphs which underlines the criticality of the conditions used. Venlafaxine hydrochloride form I is said to be obtainable by reacting a solution of venlafaxine in isopropanol and exposing the solution to gaseous HCl. The reaction mixture is cooled, filtered and dried. The yield of the product is, however, not given. An alternative method for preparing venlafaxine hydrochloride form I comprises dissolving venlafaxine hydrochloride in methanol under reflux and adding an anti-solvent selected from ethylacetate, isopropyl ether or methyl t-butyl ether and converting the obtained form III to form I by drying at about 60.degree. C.
WO 02/36542 discloses also polymorphic forms of venlafaxine hydrochloride which are designated as forms A, B, C and D and processes for their preparation.
WO 02/50017 describes the N-methylation of N,N-didesmethyl venlafaxine which can also be used in form of its formic acid salt.
WO 03/050074 describes a process for preparing venlafaxine hydrochloride form I by reacting venlafaxine with gaseous HCl in various solvents, namely ethyl acetate, acetonitrile, acetone and methylisobutyl ketone. The calculated yield of the product obtained is only 50%, based on the starting material N,N-didesmethyl venlafaxine. It is further disclosed that numerous factors are influencing the type of polymorph which is produced and its purity.
It is apparent from the above documents that most known venlafaxine hydrochloride polymorphs are prepared by using venlafaxine hydrochloride in different solvents and under different reaction conditions. Such parameters appear to play a major role in the formation of different polymorphs having different crystalline structures. These parameters may include presence of co-solvents, the temperature at which hydrochloride formation occurs, whether or not refluxing of the reaction mixture after hydrochloride formation is effected and the temperature at which the filtration of hydrochloride salt is performed.
Since venlafaxine hydrochloride is marketed as a racemate, polymorphism is to be dealt with great care, especially since the form which is more thermodynamically stable and shows desired bioavailability would be preferred over other forms considering storage conditions and shelf life. The less thermodynamically stable form is prone to convert into a more stable form and such forms are not good candidates for pharmaceutical applications, since this conversion will be noticed during the storage of the material.
It has now been surprisingly found that the process according to the invention for preparing venlafaxine hydrochloride form I allows an easy and reproducible way to obtain this product in high yields and especially important with a very high polymorphic purity.
It has further been found out that the process according to the invention for preparing venlafaxine avoids the formation of substantial amounts of by-products and proceeds quickly to completion and hence results in high yields of venlafaxine in an economical manner.